Abstract Cancer ranks as the second leading cause of death, contributing to nearly 1 in every 4 death in the US. Current cancer immunotherapies, especially checkpoint blockade, is largely influenced by PD-L1 expression in tumors; and patients with limited PD-L1 positive expression are normally less responsive to the immunotherapy. These findings suggest new technologies are needed to for PD-L1 resistant tumors. Cyclic [G(3',5')pA(3',5')p] (cGAMP) has recently emerged as an exciting new class of vaccine adjuvants, which sequentially activate innate immune responses and orchestrate adaptive immunity. Tumor associated macrophages (TAMs), a major type of immune cells in tumor microenvironment, are a potent target for adjuvant therapy. Particulate systems are ideal vehicles for targeting TAM population within tumor. Additionally, combination therapy holds great promise for tumor prevention and treatment. Most important, the critical role of cancer microbiome is gaining increased interests for cancer therapy. We hypothesize that Particulate cGAMP adjuvants targeting TAMs can enhance anti-tumor immune response and reverse the pro-tumorigenic microenvironment in both PD-L1 responsive and resistant cancers, and improve the anti-tumor efficiency in combination with checkpoint blockade and tumor resection. We have tested and will continue to test the hypothesis using B16F10 melanoma (subcutaneous and lung metastasis models; PD-L1 responsive) and C3(1)Tag basal-like breast cancer (orthotopic and spontaneous GEM models; PD-L1 resistant), and test the following specific aims: Aim 1. Particulate delivery of STING agonist as anti-cancer immuotherapeutics: (F99 phase). We optimized liposomal NP and Ace-DEX MP delivery systems for cGAMP to evaluate the cellular uptake and M2->M1 skewing capacity, and detect major histocompatibility (MHC) gene and costimulatory gene expression and cytokine production in vitro. We also investigated the tissue distribution of particulate cGAMPs and their anti-tumor efficacy in above-mentioned tumor models. Aim 2. Mechanism by which particulate delivery of STING agonist acts an as anti-cancer immuotherapeutic and combination therapies: (F99 phase). We will study the role of macrophage, CD4+ and CD8+ T cells, and NK cells in anti-tumor response of particulate cGAMPs. We will also monitor long term survival and tumor recurrence by combination therapies of particulate cGAMPs with anti-PD-L1 antibodies and tumor resection in above- mentioned tumor models. Aim 3. The Postdoctoral Research Direction (K00 phase). I will pursue my interest in understanding the mechanism and functional role of gut microbiota in host response to cancer development and therapy, meanwhile, with a particular interest in studying the role of oral microbiota in response to head and neck cancer therapeutics and restoration.